There are three recognised forms of plague in man: bubonic, septicaemic and pneumonic. All are caused by the Yersinia pestis bacterium, which has also been known as Pasteurella pestis, Bacterium pestis and Pestisella pestis. Y. pestis is endemic on every continent in the world except Australia [1], and results in around 1700 cases of plague a year. It is a Gram-negative non-motile aerobic bacillus. 
Bubonic plague is the most common form of disease and arises following a bite from a flea which has fed previously on an infected animal. From the initial site of infection the bacteria are disseminated to the draining lymph nodes, which become swollen and tender to form buboes.
Septicaemic plague occurs when there is bacteremia without the development of buboes and is characterised by an elevated temperature, chills, headache, malaise and gastrointestinal disturbances. Because of the generalised nature of these symptoms a diagnosis of plague is often delayed, and even with medical intervention 50% of patients die, probably as a result of the induction of the systemic inflammatory response syndrome.
The most feared form of plague arises when there is colonisation of the alveolar spaces leading to a pneumonia, causing the pneumonic plague. Pneumonic plague is transmitted by airborne droplets containing bacteria, generated by coughing, which can be inhaled by susceptible individuals. The pneumonic form of the disease is feared because of the rapidity with which the disease develops (1-3 days), the high mortality rate in infected individuals (about 100%) and the rapid spread of disease from man to man.
Due to the high infectivity and mortality of pneumonic plague, Y. pestis is considered to be a likely biological threat agent [2].
The only plague vaccine licensed in the United States is the ‘USP vaccine’, a preparation of formaldehyde-killed Y. pestis, but it is no longer produced. This vaccine relies on the F1 capsular protein as the main immunogen. While it has been shown to be effective against subcutaneous challenge, it is not effective against aerosol challenge [3], and unpleasant side effects have been reported. The vaccine also fails to protect against the F1− variants of Y. pestis, which are equally virulent in rodents [4, 5] and which have been isolated from at least one fatal human case [6].
More recent studies have focused on recombinant subunit vaccines. Purified or recombinant F1 antigen may confer protection against both bubonic and pneumonic plague [7], as may the V antigen [8]. The V antigen is found on the cell surface and is involved in induction of IL-10 synthesis, which contributes to the block of macrophage activation necessary for successful Y. pestis virulence [1]. Recombinant V antigen has been shown to confer protection against parenteral and aerosol challenge by both F1+ and F1− strains [8]. A fully-recombinant subunit vaccine containing both the F1 and V antigens has been formulated either with cholera toxin for transcutaneous and intradermal immunisation [9]. Three immunisations with this vaccine protected animals from a low dose injected challenge with virulent Y. pestis. The same F1/V combination has been adjuvanted with aluminium hydroxide, and confers good protection against aerosol challenge in mouse strains of different genetic background [10]. Importantly, protection was achieved after a single dose of this vaccine although the dose required was high and protective antibody titers against the V antigen required more than two months to develop [11]. For safe use in humans, reference 12 suggests that the V antigen should be altered to delete amino acid residues 271 to 300 in order to reduce immune-modulatory properties.
These studies indicate that development of an efficacious subunit vaccine based on recombinant Y. pestis proteins for use in man is feasible.
While the F1 and V antigens are promising candidates for inclusion in a prophylactic vaccine, these are the only known protective antigens against this pathogen and it is unclear if these antigens alone will afford sufficient protection in humans, or whether they would be useful in immunotherapeutic vaccines. Indeed, variability in the response to F1 in humans has been reported [13]. Reference 14 suggests that an optimal vaccine against plague should include essential virulence factors as immunogens in addition to F1. Furthermore, naturally occurring F1− strains appear to be equally virulent and with current technology it is straightforward to engineer such a strain [5], thereby bypassing any F1-based immunity. In addition, substitution of the LcrV gene in Y. pestis with that of Y. pseudotuberculosis or Y. enterocoliticus is a worry, as there is little cross protection between these different species [15]. A bivalent F1/V vaccine is therefore inadequate for use against bioterrorism.
Thus there remains a need to identify alternatives to the F1 and V antigens for use in immunising against Yersinia, and in particular for developing of a broadly-protective multivalent vaccine against all potential variant and engineered strains [2].